chr2-47480871-G-A

Variant names:

• chr2-47480871-G-A
• rs63751624
• NM_000251.3:c.2634G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.2634G>A​(p.Glu878Glu) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 8.65

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-47480871-G-A is Pathogenic according to our data. Variant chr2-47480871-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 91021.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47480871-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2634G>A	p.Glu878Glu	splice_region_variant, synonymous_variant	Exon 15 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2634G>A	p.Glu878Glu	splice_region_variant, synonymous_variant	Exon 15 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000612 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary nonpolyposis colon cancer Pathogenic:1

Aug 24, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.2634G>A (p.Glu878Glu) alters a conserved nucleotide located at the last nucleotide of exon 15 adjacent to a canonical splice donor site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by skipping on exon 15 (Perez-Cabornero_2013). The variant was absent in 251400 control chromosomes. c.2634G>A has been reported in the literature in individuals affected with Lynch Syndrome (example Perez-Cabornero_2011 and Katsidzira_2019). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic. An expert panel (InSight) has submitted clinical significance assessment for this variant as Pathogenic to ClinVar before 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome 1 Pathogenic:1

Aug 09, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 23523604]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23523604]. -

Lynch syndrome Pathogenic:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Variant causes splicing aberration leading to truncated protein: full inactivation of variant allele -

not provided Pathogenic:1

Aug 01, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted MSH2 c.2634G>A at the cDNA level. Although the variant is silent at the codinglevel, preserving a Glutamic Acid at codon 878, it is located at the last nucleotide of exon 15 and disrupts the naturalsplice donor site leading to abnormal splicing. RT-PCR studies have demonstrated that MSH2 c.2634G>A causescomplete skipping of exon 15 (Pérez-Cabornero 2013). This variant has been observed in a family meeting Amsterdamcriteria and was found to segregate with endometrial cancer in two family members. The proband's tumor displayedabsence of the MSH2 and MSH6 proteins and microsatellite instability (MSI-H) (Pérez-Cabornero 2011). MSH2c.2634G>A was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 GenomesConsortium 2015, Lek 2016). The nucleotide which is altered, a guanine (G) at base 2634, is conserved acrossspecies. Based on currently available evidence, we consider this variant to be likely pathogenic -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 878 of the MSH2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Lynch syndrome (PMID: 21778331, 23523604, 31647837; internal data). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. ClinVar contains an entry for this variant (Variation ID: 91021). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 15, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 23523604). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 28, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2634G>A pathogenic mutation (also known as p.E878E), located in coding exon 15 of the MSH2 gene, results from a G to A substitution at nucleotide position 2634. This nucleotide substitution does not change the amino acid at codon 878. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. This alteration has been identified in several individuals with Lynch syndrome-associated tumors demonstrating absent MSH2/MSH6 staining by IHC analysis and family histories meeting Amsterdam criteria (Ambry Internal Data). This mutation was reported in a Spanish woman with a MSI-H endometrial cancer that demonstrated absent MSH2 staining by IHC analysis; her family history met Amsterdam criteria. Authors subsequently used mRNA analysis to demonstrate that this alteration results in skipping of exon 15 (Pérez-Cabornero L et al. Cancer Prev Res (Phila), 2011 Oct;4:1546-55; Pérez-Cabornero L et al. J Mol Diagn, 2013 May;15:380-90). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.61		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63751624; hg19: chr2-47708010;